Implementation of subharmonic imaging on a clinical scanner for optimal ambient pressure sensitivity with SonoVue microbubbles.

Subharmonic imaging for ambient pressure estimation is a noninvasive alternative to catheter pressure measurements currently used to diagnose multiple disease processes. However, current implementations of subharmonic imaging settings lack important attributes necessary for accurate generation and detection of the subharmonic component. Some implementations employ frequencies near the resonance frequency of microbubbles, requiring high acoustic pressure to generate subharmonic signals. Others utilize short pulses (2-6 cycles) resulting in scattered spectra where the fundamental and subharmonic frequencies overlap. We investigated longer pulses at twice the resonance frequency of SonoVue microbubbles and detected the subharmonic component as a method sensitive to ambient pressure changes. We used an in-vitro pressure chamber filled with SonoVue to vary the ambient pressure (0-140 mmHg) while collecting subharmonic images. We considered multiple frequencies, pulse lengths, acoustic pressures (0-900 kPa), pulsing schemes, imaging arrays, and microbubble concentrations. Native linearized image data and radiofrequency data were used to accurately measure the subharmonic signal. Transmitting at twice the resonance frequency (4.2 MHz) results in the greatest change in subharmonic signal with ambient pressure, a 16 dB increase from 0-80 mmHg (+0.2 dB/mmHg) at 70 kPa acoustic pressure. At low acoustic pressures the sensitivity of subharmonic imaging to ambient pressure changes was not impacted by variation in microbubble concentration or image depth. Higher ambient pressures (> 100 mmHg) resulted in microbubble destruction that reduced image intensity without a change in subharmonic sensitivity. The findings in this work provide evidence of the utility of SonoVue for ambient pressure sensing at low acoustic pressures.